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GeneBe

10-102918527-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting

The NM_017649.5(CNNM2):c.47G>A(p.Gly16Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,604,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CNNM2
NM_017649.5 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.87
Variant links:
Genes affected
CNNM2 (HGNC:103): (cyclin and CBS domain divalent metal cation transport mediator 2) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg2+. Mutations in this gene are associated with renal hypomagnesemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, CNNM2
BP4
Computational evidence support a benign effect (MetaRNN=0.17726523).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000144 (22/152322) while in subpopulation NFE AF= 0.000279 (19/68022). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CNNM2NM_017649.5 linkuse as main transcriptc.47G>A p.Gly16Glu missense_variant 1/8 ENST00000369878.9
CNNM2NM_199076.3 linkuse as main transcriptc.47G>A p.Gly16Glu missense_variant 1/7
CNNM2NM_199077.3 linkuse as main transcriptc.47G>A p.Gly16Glu missense_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CNNM2ENST00000369878.9 linkuse as main transcriptc.47G>A p.Gly16Glu missense_variant 1/81 NM_017649.5 P4Q9H8M5-1
CNNM2ENST00000369875.3 linkuse as main transcriptc.47G>A p.Gly16Glu missense_variant 1/21 Q9H8M5-3
CNNM2ENST00000433628.2 linkuse as main transcriptc.47G>A p.Gly16Glu missense_variant 1/72 A1Q9H8M5-2

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000574
AC:
13
AN:
226442
Hom.:
0
AF XY:
0.0000478
AC XY:
6
AN XY:
125436
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000301
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000109
Gnomad OTH exome
AF:
0.000184
GnomAD4 exome
AF:
0.000163
AC:
237
AN:
1452094
Hom.:
0
Cov.:
31
AF XY:
0.000151
AC XY:
109
AN XY:
722312
show subpopulations
Gnomad4 AFR exome
AF:
0.0000309
Gnomad4 AMR exome
AF:
0.0000906
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000200
Gnomad4 OTH exome
AF:
0.000167
GnomAD4 genome
AF:
0.000144
AC:
22
AN:
152322
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000243
Hom.:
0
Bravo
AF:
0.000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.0000340
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023CNNM2: PM2:Supporting, PP2 -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 14, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 27, 2023This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 16 of the CNNM2 protein (p.Gly16Glu). This variant is present in population databases (rs370580602, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CNNM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1430577). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 04, 2022In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Renal hypomagnesemia 6;C4225333:Hypomagnesemia, seizures, and intellectual disability 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 13, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.025
T
BayesDel_noAF
Uncertain
-0.060
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Benign
0.021
T;.;.
Eigen
Benign
-0.11
Eigen_PC
Benign
0.081
FATHMM_MKL
Benign
0.034
N
LIST_S2
Benign
0.78
T;T;T
M_CAP
Pathogenic
0.99
D
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
0.0
N;N;N
MutationTaster
Benign
0.95
D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.0
N;N;N
REVEL
Uncertain
0.29
Sift
Uncertain
0.0030
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.0010
B;.;B
Vest4
0.14
MVP
0.15
ClinPred
0.22
T
GERP RS
4.9
Varity_R
0.42
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370580602; hg19: chr10-104678284; API